The present invention relates to the administration of a drug or other beneficial agent to a patient. More specifically, the present invention relates to the administration of a reconstituted drug or beneficial agent with a diluent to a patient.
For many applications, drugs may be mixed with a diluent before delivery to a patient. For example, it is known to mix certain drugs, prior to intravenous delivery, with a diluent such as a dextrose solution, saline solution, or even water.
It is also known, to store drugs in a powdered state and then reconstitute the drug prior to using same. For example, certain drugs can be stored for much greater periods of time if they are stored in a powder, dry, form. The drugs can be reconstituted prior to use. One method for reconstituting a drug is to utilize a syringe to inject liquid into a vial for mixing. The syringe can eventually withdraw the mixed solution from the vial.
When a drug must be diluted before delivery to a patient the drug is often injected into a container of diluent, if necessary, after it is reconstituted. The container can be connected to an administration set for delivery to a patient. For example, the diluent can be packaged in a glass bottle, or flexible plastic container such as are sold under the names MINI-BAG.TM. and VIAFLEX.RTM. by Baxter Healthcare Corporation of Deerfield, Ill. These containers have administration ports for connection to an administration set which delivers the contents of the container from the container to the patient. The drug is typically added to the container through an injection site on the container.
Drugs may be packaged separately from the diluent for various reasons. Many drugs do not retain their chemical and physical stability when mixed with a diluent. Thus, the drugs and diluent cannot be stored for a substantial period of time. Additionally, for commercial reasons, drugs are often packaged separately from the diluent because many companies which manufacture drugs are not engaged in the business of providing medical fluids in containers for intravenous delivery, and vice versa.
Therefore, it is a common practice that medical personnel must mix a drug and diluent. However, this presents a number of problems.
The reconstitution procedure is time consuming and requires aseptic technique. Often it is difficult to reconstitute the drug because the powdered drug is "caked" at the bottom of the vial. Thus, when liquid is injected into the vial from a syringe in an attempt to reconstitute the drug, the surface area of contact between the liquid and the powdered drug may initially be quite small, making the mixing procedure even more time consuming.
Because of the limited vial volume, the increasing drug concentration in the diluent makes it harder to finish the reconstitution process. The operator may attempt to solve this problem by repeatedly injecting solution into the vial, mixing and withdrawing the solution. But, this requires many additional injections and movement of the syringe within the vial which increase the likelihood of contamination. Also, it is sometimes difficult to get all of the drug and/or liquid out of the vial, thus increasing the time required to perform the reconstitution procedure.
The reconstitution procedure should preferably be performed under sterile conditions. This requirement also makes the reconstitution procedure more arduous and time consuming: sterile conditions are often hard to maintain. In some instances, a laminar flow hood may be required under which the reconstitution procedure is performed.
Some drugs, such as some chemotherapy drugs, are toxic. Exposure of the operator to the drugs during reconstitution may be dangerous, especially if the operator works with such drugs on a daily basis and is repeatedly exposed to them.
After a drug is reconstituted and withdrawn into a syringe barrel, the drug may in some instances be injected immediately into the intravenous system of a patient. More typically, however, the reconstituted drug is injected from the syringe into a larger container of solution as discussed above, for connection to an intravenous administration set.
It is typically necessary to add the reconstituted drug in the syringe to a larger volume of fluid because often the reconstituted drug in the syringe is still at a sufficiently high concentration as to cause local toxicity in the veins of a patient near the injection site where the needle pierces the skin. This can create severe vein irritation which can be harmful to the patient.
Additionally, even though the proper dose of medication is in the syringe, immediate injection into the patient's blood stream can create a condition of systemic toxicity wherein the level of drug concentration in the patient's entire blood stream is dangerously high. Additionally, injection from the syringe directly into the patient requires an additional injection into the patient, which can be painful for the patient and provides another opportunity for infection.
For these reasons, the reconstituted drug is more typically injected into a diluent container.
A patient is typically administered a dextrose or saline solution from a large volume parenteral container, for example, such as a one liter container, delivered through an administration set such as a CONTINU-FLO.RTM. administration set sold by Baxter Healthcare Corporation. If the reconstituted drug were injected into such a large volume parenteral container, delivery of the drug would usually be made over too long a time period. Often, these large volume fluids are delivered at very slow flow rates.
It is also known to inject the reconstituted drug into a small volume parenteral container, such as a fifty milliliter container sold by Baxter Healthcare Corporation. This MINIBAG.TM. container is then supported at a higher elevation than a larger volume parenteral container and is connected by a secondary administration set to an injection site on the primary administration set. Because it is maintained at a higher elevation, the reconstituted drug in the small volume container is delivered, after which fluid from the large volume container begins to flow once more. By utilizing a small volume container connected to an administration set for delivery of the drug or other beneficial agent, instead of a direct syringe injection, the drug is delivered over a preferred time period that tends to minimize negative side effects.
Reconstitution and drug delivery systems are also known. A closed reconstitution delivery system is disclosed in U.S. Pat. No. 4,410,321; U.S. Pat. No. 4,411,662; U.S. Pat. No. 4,432,755; and U.S. Pat. No. 4,458,733, all assigned to Baxter International Inc., the assignee of the present invention. As shown therein, a container includes a drug and a diluent in separate compartments which are reconstituted in a closed system before the drug is delivered to the patient. Typically, the container is connected to an administration set which is connected at its other end to the primary administration set, such as with the small volume parenteral container described above. The container shown in these patents solves many of the problems associated with syringe reconstitution. The product does, however, necessitate a series of reconstitution steps which must be performed by the nurse or other operator prior to delivering the fluid from the container.
U.S. Pat. No. 4,424,056; U.S. Pat. No. 4,432,756; U.S. Pat. No. 4,439,183; U.S. Pat. No. 4,474,574; U.S. Pat. No. 4,479,793; U.S. Pat. No. 4,479,794; U.S. Pat. No. 4,525,162; and U.S. Pat. No. 4,548,599 and Canadian Patent No. 1,173,795, assigned to Alza Corporation of Palo Alto, California disclose a parenteral delivery system which has a formulation chamber therein for administering a beneficial agent such as a drug. The system provides for reconstitution of the drug by fluid flowing from a large volume parenteral container for example, through the administration set containing the formulation chamber with the drug therein.
Another passive reconstitution system is disclosed in European Patent Application No. 0059694 to Aktiebolaget Hassle of Sweden.
Still another device for delivering a drug "in-line", i.e., in the administration set, is disclosed in U.S. Pat. No. 4,534,757 assigned to Alza Corporation. The device holds the drug and includes a section through which the liquid passes in a direction substantially opposite to the general direction in which liquid flows to the patient.
Yet another system which attempts to provide for drug reconstitution in-line without manual reconstitution by a nurse or other operator is shown in U.S. Pat. No. 4,465,471, assigned to Eli Lilly and Co. of Indianapolis, Indiana. That patent discloses constructions for a receptacle in the administration set itself. A separate cartridge containing the drug to be reconstituted and delivered to the patient is plugged into the receptacle.
European Patent Application Publication No. 0146310 to Eli Lilly and Co., corresponding to U.S. Pat. No. 4,573,967, is directed to a system for drug reconstitution including an intravenous administration set and a drug vial and utilizes a vial vacuum to reconstitute the drug.
U.S. Pat. No. 4,534,758 to Akers et al. discloses a relatively complex drug delivery apparatus with various valves. When liquid from a container is delivered to the drug vial, the vial is to be agitated for a time sufficient to suspend the previously dry medicine.
U.S. Pat. No. 4,581,014 to Millerd et al., assigned to Ivac Corporation of San Diego, California discloses a selector valve for delivering a previously reconstituted drug from a drug vial through an intravenous administration set to a patient.
All the publications described above are directed to solutions to the time consuming reconstitution procedure and/or its associated problems, such as delivery of the solution to a patient. In most of the offered solutions, delivery of the drug is intended to be passive, i.e., once the drug is placed into the administration set, manual reconstitution steps are not required.
Israel U.S. Pat. No. 4,589,867 discloses a delivery apparatus including an integral diluent container and a mixing container with an upward flow path.
Ridell U.S. Pat. No. 4,623,334 discloses delivery of a drug from an add-on vial. Israel and Riddell are principally directed to delivering liquid having a decreasing drug concentration over time, to a patient.
Ogle U.S. Pat. No. 3,941,171 is directed to a fluid transfer device including an adapter for connecting a chamber having a pierceable closure with another container.
Still another common feature of many of the attempted solutions disclosed in these publications is that delivery of the drug is intended to be able to be made in a manner which is essentially independent of the fluid flow rate through the administration set and into the patient. Stated differently, some of the systems are designed to deliver a certain dosage of drug in a preselected time period, within a broad range of fluid flow rates. Delivery of a drug independent of flow rate is desirable because it ensures that the necessary dosage will be delivered within a therapeutically acceptable time period, which may be typically about twenty to thirty minutes, although this time period may vary depending upon the drug and dosage.
By making delivery of the drug or other beneficial agent independent of the flow rate, the system ensures that the drug will not be delivered too quickly should the flow rate be set too high by the nurse or other operator, thereby preventing the problem of systemic toxicity discussed above.
Some of the documents, such as U.S. Pat. No. 4,424,056; U.S. Pat. No. 4,479,793; and U.S. Pat. No. 4,479,794 are also directed to systems having a beneficial agent placed "in-line" in an administration set for mixing of the agent and delivery to a patient, wherein the delivery of the agent may be made in a given volume of fluid. Also, a valve controlling fluid flow may be manually operated to deliver the agent in a manner which can be made dependent upon fluid flow.
U.S. Pat. No. 4,850,978 discloses a system that includes a cartridge for introducing a beneficial agent into a fluid conduit for delivery of the agent to a patient. The cartridge includes a rigid hollow tube and an agent-containing chamber slidably mounted at least partially within the hollow tube. In a first, pre-use position, the chamber extends farther from the hollow tube than it does in a second position. A cannula is mounted to the hollow tube extending opposite the chamber. When the chamber is in the second position, the cannula pierces the closure means creating a fluid flow path.
U.S. Pat. No. 4,804,366 also discloses a drug delivery system including an adapter having an improved flow path means provided both at an inlet and an outlet to the agent-containing chamber of a cartridge. The cartridge and adapter permit a single opening through the injection sites at opposite ends of the flow path means, while still permitting simultaneous flow both into and out of the chamber. An adapter and a cartridge is provided, including a rigid cannula with an inlet and an outlet in a shell substantially coaxial with and spaced from the cannula intermediate of the cannula inlet and the cannula outlet so that the shell of the cannula define a channel therebetween. Both the cannula inlet and the cannula outlet are adaptable to form a single piercing opening in a resilient injection side associated with the receptacle of the delivery system. Both the channel outlet and channel inlet are adapted to form a single piercing opening in a resilient injection site associated with the cartridge.